Risk factors for loss to follow-up of persons who inject drugs enrolled at syringe services programs in Kentucky.

BACKGROUND: Syringe services programs (SSP) are an effective strategy to reduce blood-borne infections of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in persons who inject drugs (PWID). The objectives of this study were to determine the frequency and risk factors for loss to follow-up (LTFU) in PWID enrolled at SSPs in Kentucky. METHODS: A retrospective cohort study was conducted which included data of PWID enrolled at 32 SSP. Demographics, use of drugs, HIV testing, HCV testing, and medical services were analyzed. A generalized linear model (GLM), family binomial was used to determine risk factors for LTFU. RESULTS: The analysis included 5742 PWID. LTFU by year of enrollment was 287/770 (37.3%) in 2017, 796/1874 (42.5%) in 2018, and 1479/3,098 (47.7%) in 2019. LTFU was significantly associated with distance to SSP from home of more than five miles (RR 1.25; 95%CI 1.09-1.43; p = 0.002) and SSPs housed in rural counties (RR 1.22; 95%CI 1.06-1.40; p = 0.004), adjusted by age, sex, and race. The use of buprenorphine was associated with less risk of LTFU (RR 0.79, p = 0.034). CONCLUSION: The distance to an SSP from home and SSPs in rural counties were identified as risk factors for LTFU. Initiatives that bring health services closer to PWID homes and offer opioid use disorder treatment may improve repeated participation in SSPs.

Molecular activation of the NLRP3 Inflammasome in fibrosis: common threads linking divergent fibrogenic diseases.

SIGNIFICANCE: Over the past 10 years, there has been a plethora of investigations centering on the NLRP3 inflammasome and its role in fibrosis and other disease pathologies. To date, the signaling pathways from the inflammasome to myofibroblast differentiation and chronic collagen synthesis have not been fully elucidated, and many questions are left to be answered. RECENT ADVANCES: Recent studies have demonstrated the significant and critical role of reactive oxygen species (ROS) and calcium signaling in the assembly of the inflammasome, and this may result in autocrine signaling maintaining the myofibroblast phenotype, leading to fibrotic disease. CRITICAL ISSUES: Traditionally, myofibroblasts under tight regulation aid in wound healing and then, once the wound has closed, undergo apoptosis and the collagen in the wound remodels. During fibrosis, however, the myofibroblast maintains an activated state via a chronically activated inflammasome, leading to the continual synthesis of collagens and other extracellular matrix proteins that result in damage to the tissue or organ. The mechanism that is driving this abnormality has not been fully elucidated. FUTURE DIRECTIONS: However, studies have been conducted to suggest that modulating the calcium or the ROS axis may be of therapeutic value in regulating inflammasome activation. A number of novel drugs are currently being developed that may prove beneficial to patients suffering from fibrotic diseases.

Targeting the unfolded protein response, XBP1, and the NLRP3 inflammasome in fibrosis and cancer.

Increasing health care costs in the US are due in a large part to the increasing prevalence of chronic diseases in an aging population. Current therapeutic strategies for treating chronic diseases alleviate symptoms allowing patients to live longer with these diseases, but they do little, however, to alter the underlying disease course. Recent advances in molecular biology are revealing new drug targets that may significantly alter the course of these diseases and, as a result, offer economic relief from burgeoning health care costs. Endoplasmic reticulum (ER) stress has been implicated as an underlying pathology in many chronic diseases, and, therefore, the development of therapies designed to ameliorate ER stress may yield novel, effective treatment strategies. Herein, we report that X-box binding protein 1 (XBP1) may be one of the earliest proteins engaged in response to ER stress. We show that a new signaling peptide derived from the ER-embedded transient receptor potential calcium channel protein 1 (TRPC1) engages XBP1 upstream of NLRP3 inflammasome-mediated maturation and secretion of IL-1ß/IL-18. Moreover, we show that a synthetic homolog of this signaling peptide (Naclynamide™) administered intravenously twice weekly over a 4-week treatment course induced suppuration and evoked partial or complete resolution of lesions associated with a fibrotic granuloma, a lymphosarcoma, and a colo-rectal carcinoma in canine patients. The mode of action for Naclynamide™ as a first-in-class anti-cancer drug candidate is discussed.

NLRP3 inflammasome is a target for development of broad-spectrum anti-infective drugs.

We describe the molecular mode of action and pharmacodynamics of a new molecular entity (NME) that induces the NLRP3 inflammasome-mediated innate immune response. This innate response reduces the pathogen load in an experimentally induced methicillin-resistant Staphylococcos aureus infection, enhances survival in an experimentally induced Gram-negative bacteremia, and overrides the escape mechanism of an obligate intracellular pathogen, viz. Chlamydia pneumoniae. Furthermore, the NME is more effective than standard-of-care antibiotic therapy in a clinically established multifactorial bacterial infection. Analysis of transcriptional regulation of inflammasome signaling genes and innate/adaptive immune genes revealed consistent and significant host changes responsible for the improved outcomes in these infections. These studies pave the way for the development of first-in-class drugs that enhance inflammasome-mediated pathogen clearance and identify the NLRP3 inflammasome as a drug target to address the global problem of emerging new infectious diseases and the reemergence of old diseases in an antibiotic-resistant form.

Evolving minimally invasive spine surgery: a surgeon's perspective on technological convergence and digital or control system.

Degenerated spinal disc and spinal stenosis are common problems requiring decompressive spinal surgery. Traditional open spinal discectomy is associated with significant tissue trauma, greater morbidity/complications, scarring, often longer term of convalescence, and even destabilization of the spine. Therefore, the pursuit of less traumatic minimally invasive spine surgery (MISS) began. The trend of spinal surgery is rapidly moving toward MISS. MISS is a technologically dependent surgery, and requires increased utilization of advanced endoscopic surgical instruments, imaging-video technology, and tissue modulation technology for performing spinal surgery in a digital operating room (DOR). It requires seamless connectivity and control to perform the surgical procedures in a precise and orchestrated manner. A new integrated DOR, the technological convergence and control system SurgMatix(R), was created in response to the need and to facilitate MISS with "organized control instead of organized chaos" in the endoscopic OR suite. It facilitates the performance, training, and further development of MISS.

1-Peptidyl-2-arachidonoyl-3-stearoyl-sn-glyceride: an immunologically active lipopeptide from goat serum (Capra hircus) is an endogenous damage-associated molecular pattern.

Experiments were undertaken to isolate a component of the serum of goat (Capra hircus) that is effective at mediating an innate immune response. This report describes the isolation and structure elucidation of 1-(N-acetyl-ALYDKGYTSKEQKDCVGI)-2-arachidonoyl-3-stearoyl glyceride (1) and its immunomodulatory activity. A dose-response relationship for inflammatory cytokine and chemokine production and release from human fibroblasts incubated with nanomolar concentrations of 1 was shown. Moreover, the membrane transport role of the diacylglycerol moiety in 1 is demonstrated with nanomolar quantities of the transfected N-acetyl peptide moiety of 1 also inducing inflammatory cytokine and chemokine production and release. The apparent EC99 for 1 was 3 ng/mL (1 nM). The likely biological role for naturally occurring 1 as a damage-associated molecular pattern is postulated.